The main objectives of this project are to quantify the pathways of catecholamine metabolism in experimental animals and humans and establish the involvement of disturbances in these pathways in certain disease processes. Tissue, plasma or urine samples are obtained before and during pharmacological or physiological manipulations and analyzed for concentrations of endogenous and exogenous radiolabelled catecholamines and their metabolites. Findings in experimental animals are consistently demonstrating that neuronal pathways predominate over extraneuronal pathways for inactivation of the norepinephrine released by sympathetic nerves. A similar trend is emerging in ongoing studies in humans and swine where it is also possible to examine how the regional disposition of catecholamines is integrated among different organs and tissues. Of particular relevance the liver removes much of the norepinephrine, dopamine, and metabolites that are formed and released within the gastrointestinal tract, thereby hiding the true extent of the production of these catecholamines in mesenteric organs. The possibility that the much larger amounts of dopamine than norepinephrine metabolites produced in the lungs and gastrointestinal tract might reflect the existence of a third previously unknown non-noradrenergic catecholamine system is being actively explored. Findings in experimental animals that show how inhibition of the two A and B forms of monoamine oxidase cause different increases in O-methylated metabolites and decreases in the deaminated metabolites are being extended to studies of the involvement of these metabolizing enzymes in various neurological and behavioral disorders.